London Research Institute
  • London, United Kingdom
Recent publications
Previous studies have suggested that systemic viral infections may increase risks of dementia. Whether this holds true for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infections is unknown. Determining this is important for anticipating the potential future incidence of dementia. To begin to do this, we measured plasma biomarkers linked to Alzheimer’s disease pathology in the UK Biobank before and after serology-confirmed SARS-CoV-2 infections. SARS-CoV-2 infection was associated with biomarkers associated with β-amyloid pathology: reduced plasma Aβ42:Aβ40 ratio and, in more vulnerable participants, lower plasma Aβ42 and higher plasma pTau-181. The plasma biomarker changes were greater in participants who had been hospitalized with COVID-19 or had reported hypertension previously. We showed that the changes in biomarkers were linked to brain structural imaging patterns associated with Alzheimer’s disease, lower cognitive test scores and poorer overall health evaluations. Our data from this post hoc case–control matched study thus provide observational biomarker evidence that SARS-CoV-2 infection can be associated with greater brain β-amyloid pathology in older adults. While these results do not establish causality, they suggest that SARS-CoV-2 (and possibly other systemic inflammatory diseases) may increase the risk of future Alzheimer’s disease.
This study explores directional selection on physical and psychosocial phenotypes in Eastern Eurasian populations, utilizing a dataset of 1245 ancient genomes. By analyzing polygenic scores (PGS) for traits including height, educational attainment (EA), IQ, autism, schizophrenia, and others, we observed significant temporal trends spanning the Holocene era. The results suggest positive selection for cognitive-related traits such as IQ, EA and autism spectrum disorder (ASD), alongside negative selection for anxiety and depression. The results for height were mixed and showed nonlinear relationships with Years Before Present (BP). These trends were partially mediated by genetic components linked to distinct ancestral populations. Regression models incorporating admixture, geography, and temporal variables were used to account for biases in population composition over time. Latitude showed a positive effect on ASD PGS, EA and height, while it had a negative effect on skin pigmentation scores. Additionally, latitude exhibited significant nonlinear effects on multiple phenotypes. The observed patterns highlight the influence of climate-mediated selection pressures on trait evolution. Spline regression revealed that several polygenic scores had nonlinear relationships with years BP. The findings provide evidence for complex evolutionary dynamics, with distinct selective pressures shaping phenotypic diversity across different timescales and environments.
The applications of artificial intelligence (AI) and deep learning (DL) are leading to significant advances in cancer research, particularly in analysing histopathology images for prognostic and treatment-predictive insights. However, effective translation of these computational methods requires computational researchers to have at least a basic understanding of histopathology. In this work, we aim to bridge that gap by introducing essential histopathology concepts to support AI developers in their research. We cover the defining features of key cell types, including epithelial, stromal, and immune cells. The concepts of malignancy, precursor lesions, and the tumour microenvironment (TME) are discussed and illustrated. To enhance understanding, we also introduce foundational histopathology techniques, such as conventional staining with hematoxylin and eosin (HE), antibody staining by immunohistochemistry, and including the new multiplexed antibody staining methods. By providing this essential knowledge to the computational community, we aim to accelerate the development of AI algorithms for cancer research.
Background Personal health records (PHRs) or patient portals have been on the healthcare policy agenda for many countries as a promising mechanism to support patient-centred healthcare by making medical records accessible to patients and those assisting patients in health self-management. Studies on clinical outcome have been inconsistent. To help us to understand why, we propose to look at measures that precede clinical outcome, specifically patient engagement and activation. Patient activation describes the knowledge, skills and confidence a person has in managing their own health and healthcare. Objective To systematically review the current evidence on the impact of PHRs on patient activation. Methods A literature search was conducted for randomised controlled trials and quasi-experimental studies published up to January 2024 across EMBASE, PsycINFO, CINAHL and PubMed. Publications were included in the study if they examined any association between PHR use and activation. Results The search initially produced 3062 papers for review, of which 88 full-text articles were screened for eligibility. Two reviewers assessed 22 of these articles, and 8 papers were identified as meeting the selection criteria. Among these, seven studies found no statistically significant differences in activation. However, one study reported a significantly greater effect than the others. Data from seven randomised controlled trials and quasi-experimental studies examining the effects of PHRs on patient activation and similar measures were extracted for meta-analysis. Overall, the use of PHRs was associated with a 0.41 standardised mean difference increase in activation (95% confidence interval 0.31–0.51). There was a high degree of heterogeneity (I² = 98%), with one study showing a much larger effect size compared to the rest. Conclusion Most studies showed little impact on activation, but one study found a large effect. This study notably offered PHRs combined with health coaching and training in the use of the system to their intervention group, which may indicate an important requirement for how to get the best out of a PHR system.
Importance Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.
Aim To develop and test a Family and Community Nursing—Advanced Practice Scale. Design A cross‐sectional and methodological scale validation design, following classical test theory. Methods Three phases, the first of which involved scale development, including item generation. Phase two assessed the content validity index. The third phase involved a cross‐sectional survey to establish construct validity, content validity, internal consistency reliability, and exploratory factor analysis. Results The Family and Community Nursing Advanced Practice Scale has good construct validity, with the final scale consisting of 5 domains and 27 items. This was confirmed by both the exploratory and confirmatory factor analysis. The Cronbach's Alpha is very good, suggesting that the scale is reliable. When comparing family practice advanced practice nurses with those working in the community, the results show that scores are similar except for clinical reasoning and health promotion, which consistently showed statistically significant higher scores among the family practice nurses. While community nurses scored higher on items in the leading practice domain reflecting their role in a wider team of nurses. Conclusion This study developed and psychometrically tested the Family and Community Nursing—Advanced Practice Scale. The scale has good reliability, and analysis of the construct validity reveals five domains of advanced practice among this practitioner group. Implications for the Profession The study suggests that advanced practice nurses working in community roles perform similar activities to those working in family practice in the United Kingdom. However, activity related to research was less evident. Impact The study examined the scope of the advanced practice nurse role in family and community nursing. The study illustrated practice across five domains: clinical care, leading practice, clinical reasoning, health promotion, and ethics. The family practice and wider community roles were largely homogenous, with only two items showing a statistically significant difference in scores. Reporting Method STROBE guidelines for cross‐sectional studies. Patient or Public Contribution No patient or public contribution.
Background/Objectives: Given the magnitude and urgency of the global antimicrobial resistance (AMR) problem and the insufficiency of strategies to reduce antimicrobial use, there is a need for novel strategies. Traditional, Complementary, and Integrative Healthcare (TCIH) provides strategies and solutions that contribute to reducing (inappropriate) antimicrobial use, preventing or treating infections in both human and veterinary medicine, and may contribute to promoting the health/resilience of humans and animals and reducing AMR. The aims of this study were to present the core results of a global TCIH research agenda for AMR and its added value to two existing global AMR research agendas published in 2023. Methods: A survey, interviews, and consensus meetings among network members, as an adapted version of the nominal group technique, were executed to develop the global TCIH research agenda. A comparison of the global TCIH research agenda with the two existing global AMR research agendas was performed. The TCIH additions to these two existing global AMR research agendas were determined. Results: The global TCIH research agenda adds to 19 of 40 research priorities of the World Health Organization (WHO) AMR research agenda 2023 and three of the five pillars of the WHO/Food and Agriculture Organization of the United Nations (FAO)/United Nations Environment Programme (UNEP)/World Organisation for Animal Health (WOAH) research agenda 2023. In addition, the TCIH research agenda adds two new research themes with four new research priorities and three new research priorities to already existing themes of the two global AMR research agendas. Conclusions: The global TCIH research agenda fits with and adds to two global AMR research agendas and can be used as an additional strategy to reduce AMR and (inappropriate) use of antibiotics.
Background. Music therapy (MT) has been shown to be effective for multiple clinical endpoints in clients with Substance Use Disorder (SUD). However, a gap remains in understanding the impact of MT interventions in community services, primarily due to the lack of studies that combine neural measures (e.g., EEG), psychometric tests, and semi-structured interviews. Methods. This pilot study is a three-arm, non-blinded, mixed-methods randomized trial. Sixteen participants with Substance Use Disorder (SUD) were recruited from a community service in London. Ten of these participants received six weekly group or individual music therapy (MT) sessions in addition to the standard treatment (ST) provided by the community outpatient service. The remaining six participants received only the ST. Pre-/post-intervention as well as in-session measures have been collected utilizing EEG in addition to psychometric tests and semi-structured interviews addressing craving, depressive, and anxiety symptoms, inhibitory cognitive control, and participants’ perceptions on the music-therapeutic process. An intention-to-treat approach was employed. Results. Fourteen participants completed the study. Results showed (1) lower beta frequency band related to craving arousal post-MT intervention as compared to ST; (2) lower subjective evaluation of craving intensity after MT sessions; (3) different impact of MT and ST on frontal alpha asymmetry related to affective processing; (4) enhanced neural mechanisms (i.e., P3d in a Go/NoGo task) related to sensorimotor response inhibition following MT; (5) qualitative themes reflecting absence of craving, reluctance towards craving discussions, narratives on experiences, emotions, and the therapeutic process. Conclusions. MT might facilitate lower post-intervention arousal related to craving as compared to ST. While this effect is evident at the neural level, the conscious perception of the decrease emerges only after MT sessions and not after the entire intervention. The differential brain asymmetry may represent higher emotional regulation and introspection associated with MT compared to ST. MT may facilitate neuromodulation that boosts inhibitory cognitive control functions. Themes emerging from semi-structured interviews highlight the transformative potential of MT in alleviating craving and stimulating reflection. Findings from this pilot study are promising but further research through a larger clinical trial is necessary to confirm and expand upon this pilot. Trial registration. NCT05180617.
Background Data from high‐income countries (HICs) suggest a decline in age‐specific incidence rates of dementia. However, this has happened primarily in HICs, with low‐ and middle‐ income countries (LMICs) facing two main challenges: a higher burden of risk factors and, in general, a faster ageing population. Most people with dementia live in LMICs, and this is set to increase, thus requiring urgent and robust action to prevent, treat and support people with dementia and their families. Methods We, in the Lancet Commission, reviewed the most recent literature, and conducted a new metanalysis on worldwide dementia risk. We have calculated worldwide figures, although there may be variation in different ethnic and socioeconomic groups. Results Dementia studies are overwhelmingly from HICs, and there is a tendency to recruit people of European origin with higher education and socioeconomic status, with few people from ethnic minority groups. The same applies in respect of worldwide clinical trials, including multicomponent interventions to reduce risk, biomarker research and pharmacological/non‐pharmacological interventions. Although most interventions are developed in HICs, culturally adapted interventions seem to be as effective in LMICs as in their original context, as long as the interventions’ core components are not compromised in the adaptation process. Conclusion Policy interventions can improve dementia prevention, particularly in LMICs and in minority and lower level socio‐economic groups ‐ precisely the people who have the greatest burden of modifiable risk and are more likely to develop dementia. Dementia prevention efforts should be tailored to the needs of the different countries and different groups within countries. Trials and research databases should aim for sociodemographic diversity to reflect real life populations. Although evidence‐based interventions developed in HICs can be effective in LMICs, there is often a lack of healthcare infrastructure and resources to deliver them. Moreover, cultural differences can make them inappropriate or less effective. Interventions should be developed in partnership with local communities to ensure their appropriateness in respect of the culture, beliefs and practises which vary within and between countries.
Background The progressive nature of dementia and the complex needs means that people living with dementia require tailored approaches to address their changing care needs over time. These include physical multimorbidity, psychological, behavioural, and cognitive symptoms and possible risks arising from these and helping family caregivers. However, provision of these interventions is highly variable between and within countries, partly due to uncertainty about their efficacy and scarce resources. In the 2024 update of the Lancet Commission we aimed to summarise published evidence about the effect of non‐pharmacological interventions for people with dementia and their carers on cognition, neuropsychiatric symptoms and other person‐centred outcomes. Method We reviewed and summarised evidence according to expert consensus opinion. Result There is moderate‐quality evidence from a Cochrane review of 25 studies for effect of cognitive stimulation therapy on cognition; 1.99 (1.24‐2.74) Mini‐Mental State Examination points higher compared to control groups, and clinically relevant improvements in communication and social interaction. Multicomponent interventions for family carers reduce family carer depression, burden, or stress and are cost‐effective but remote delivery of these interventions was not better than care as usual. A meta‐analysis of 7 studies of tailored activity programmes for people with dementia found a moderate effect on improving quality of life (standardised ES Cohen’s d 0.79, 0.39–1.18; 7 studies, n = 160), decreasing neuropsychiatric symptoms (0.62; 0.40–0.83) and decreasing carer burden (0.68, 0.29–1.07) but there is little evidence on cost‐effectiveness. Exercise interventions were not effective in improving neuropsychiatric symptoms, cognition or functioning. We discuss evidence for other treatments for specific neuropsychiatric symptoms. Conclusion There is developing evidence for benefit of psychological and social interventions on key outcomes including cognition, neuropsychiatric symptoms and quality of life, with sufficient strength of evidence and cost‐effectiveness to justify these being implemented and offered routinely to people with dementia. Interventions generally should be tailored to specific symptoms and individualised to patient preferences and goals. Most interventions have been tested in majority ethnic populations in high income countries: future interventions should be co‐designed with local communities to ensure that they are appropriate for the context, culture, beliefs and practices.
Background In the brain as in other organs, complement contributes to immune defence and housekeeping to maintain homeostasis. Sources of complement may include local production by brain cells and influx from the periphery, the latter severely restricted by the blood brain barrier (BBB) in healthy brain. Dysregulation of complement leads to excessive inflammation, direct damage to self‐cells and propagation of injury. This is likely of particular relevance in the brain where inflammation is poorly tolerated and brain cells are vulnerable to direct damage by complement. Method We have developed novel anti‐C7 antibodies (mAb) that efficiently inhibit formation of the pro‐inflammatory membrane attack complex (MAC) in vitro and in vivo. Here we describe recombinant fusion proteins (FP) that replicate the MAC‐blocking action of the mAb, and are designed to access the brain utilising “Trojan horse” shuttles. The Alzheimer model APPNL‐G‐F mice were treated systemically with native mAb to swamp peripheral C7 followed by the FP. Immunohistochemistry and ELISA were used to demonstrate FP entry into brain and show impact on the disease pathology. Result The recombinant FP showed complement inhibitory activity in vitro equivalent to their parent mAb and were able to cross an artificial BBB in transwells. The presence of the FP in brain homogenates of peripherally dosed animals was confirmed by ELISA. Treatment with the FP caused reduced levels of complement activation products C3b and terminal complement complex (TCC) in brain. Diolistics analysis showed significant increased neuronal spine density in treated mice compared to controls, demonstrating a protective effect of the FP on synaptic function. Mice treated with the drug showed significant improvements in cognition. Conclusion The FP described are able to cross BBB and are potent inhibitors of complement in brain; impact on brain pathology was detected after just one week of treatment. The findings highlight the potential for complement inhibition as a therapy in Alzheimer’s disease.
The recent positive phase 3 clinical trials of new treatments and their licensing and roll‐out in the US and other countries represents a major turning point in Alzheimer’s disease research. As has been the case with many other diseases, e.g. multiple sclerosis and stroke, it is hoped that these successes will act as a catalyst, spurring the development not only of the next generation of amyloid immunotherapies but a range of other therapeutic approaches targeting different aspects of Alzheimer pathology, and different forms of dementia. How future trials are designed will likely have major impacts on their chances of success but also how they are deployed when licensed in clinical practice. It is of course vital that trials are designed to prioritise patient safety and use robust methodologies to produce valid results while maximising the possibility of gaining insights into mechanisms and any side‐effects. However, it is also imperative that protocols are acceptable to participants, and designed wherever possible to maximise compliance, improve accessibility, reduce cost and increase representativeness. Factors that need to be considered include those which may be dependent on the drug’s mode of action and likely effect, e.g. the length of the trial, the method of trial drug delivery, and any requirements for safety monitoring. Factors where there may be scope for change include, but are not limited to, the required number of trial visits, the length of assessments (e.g. including shorter MRI protocols for safety monitoring), the possibility of remote or at home as opposed to in‐hospital visits where possible, and simplifying methods for determining molecular pathology both as entry and potentially stopping criteria (e.g. if plasma can be used instead of CSF or molecular imaging). If we are to maximise the reach of our trials, ensure they are truly representative of all the people who might benefit, and increase recruitment rates, it is vital that we engage with study participants in the design of future studies, engage them as advocates for our research, and promote and actively involve individuals from diverse and under‐represented backgrounds.
Background The locus coeruleus (LC)‐norepinephrine (NE) system is one of the first systems affected in Alzheimer’s Disease (AD), prior to cortical involvement. LC‐NE system dysregulation has also been associated with neuropsychiatric and stress‐related symptoms, early non‐cognitive signals of AD. This study investigates whether structural and functional LC‐NE system metrics are associated with affective and stress‐related reports among predominantly cognitively healthy adults, and whether these associations are exacerbated by AD fluid biomarkers of tau, neurodegeneration and astrocyte reactivity. Method Cross‐sectional data from 116 life‐span study participants (cognitively healthy/MCI: N = 114/2; age range = 30‐87 years; female = 53%; Table 1) who completed affective (DASS–Stress, DASS–Anxiety, HDRS) and stress‐related (MIA–Anxiety, Perceived Stress Scale (PSS), NEO PI‐R–Neuroticism, DASS–Stress) questionnaires. Plasma 3‐methoxy‐4‐hydroxyphenylethyleneglycol (MHPG) and AD‐related markers (ptau217, ptau231, NfL, or GFAP), and 7T LC‐MRI scanning were obtained. MHPG was normalized against NE. LC MRI signal intensity was obtained using an MT‐TFL sequence, standardizing LC signal to the pontine tegmentum (reference), and creating a study‐specific LC template. Bootstrapped linear regression examined associations of affective and stress‐related questionnaires with LC MRI signal intensity alone, or interacted with AD markers. Linear regressions assessed equivalent associations with MHPG instead of LC MRI signal intensity. Analyses were based on complete cases, corrected for age and sex, and FDR‐adjusted. Results Lower LC MRI signal intensity related to higher DASS–Anxiety scores (pFDR = 0.008; Table 2/Fig. 1A). This relationship was more pronounced in individuals with higher ptau217 (pFDR = 0.002), ptau231 (p = 0.028), NfL (pFDR = 0.002) or GFAP (pFDR = 0.002; Table 2/Fig. 1B‐E). Higher MHPG was linked to higher PSS scores in individuals with elevated GFAP, while higher MHPG was associated with lower PSS in the context of lower GFAP (p = 0.029, Table 2/Fig. 1F). Conclusion This work suggests that structural and functional LC‐NE system metrics are distinctly related to stress and affective functioning. Lower structural LC integrity is associated with worse anxiety, particularly at elevated AD pathology levels. Among individuals with elevated astrocyte reactivity, higher LC metabolism is no longer protective against stress. These findings are consistent with previous autopsy and metabolite studies, and support the importance of the LC‐NE system in neuropsychiatric symptoms as the earliest AD manifestations.
Background In light of the poor fold change in the plasma amyloid‐β (Aβ) 42/amyloid‐β 40 ratio (Aβ42/40) between Alzheimer’s disease (AD) and control (CTRL) cases, novel Aβ biomarkers are needed which will require harnessing the increased sensitivity offered by a novel modification to the Quanterix Corporation Single molecule array (Simoa) technology. Method Simoa assays for the detection of Aβ43 and pyroglutamate‐modified Aβ 3‐40 (AβpE3‐40) have been developed on the standard HD‐X instrument. Aβ43 and AβpE3‐40 were measured in 8 CSF samples (1 AD, 4 mixed phenotype [MP] and 3 CTRL) on the HD‐X instrument, each of which were measured at four dilution levels – neat, 2x, 4x and 8x dilution. Result Out of a possible 32 measurements per analyte (four dilution levels per sample), Aβ43 was quantifiable in 68.8% of measurements, 72.7% of which fell below the concentration of calibrator B. In three samples, Aβ43 was measurable at all four dilution levels, and showed a strong but statistically non‐significant dilution linearity. In contrast, AβpE3‐40 was quantifiable in 93.8% samples, 96.6% of which fell below the concentrations of calibrator B. In six samples, AβpE3‐40 was measurable at all four dilution levels. One sample showed a strong but statistically non‐significant dilution linearity, with the remaining five samples showing a poor dilution linearity, suggesting the limits of HD‐X sensitivity had been reached. Conclusion The increased sensitivity provided by the modification to the Simoa SRx is needed to accurately quantify Aβ43 and AβpE3‐40 in CSF and subsequently plasma. Work is ongoing to transfer these novel assays from the HDx onto the modified SRx instrument.
Background Tau‐PET imaging allows in‐vivo detection of neurofibrillary tangles. One tau‐PET tracer (i.e., [18F]flortaucipir) has received FDA‐approval for clinical use, and multiple other tau‐PET tracers have been implemented into clinical trials for participant selection and/or as a primary or secondary outcome measure. To optimize future use of tau‐PET, it is essential to understand how demographic, clinical and genetic factors affect tau‐PET‐positivity rates. Method This large‐scale multi‐center study includes 9713 participants from 35 cohorts worldwide who underwent tau‐PET with [18F]flortaucipir (n = 6420), [18F]RO948 (n = 1999), [18F]MK6240 (n = 878) or [18F]PI2620 (n = 416) (Table‐1). We analyzed individual‐level tau‐PET SUVR data using a cerebellar reference region that were processed either centrally (n = 3855) or by each cohort (n = 5858). We computed cohort‐specific SUVR thresholds based on the mean + 2 standard deviations in a temporal meta‐region of amyloid‐negative cognitively normal (CN) individuals aged >50. Logistic generalized estimating equations were used to estimate tau‐PET‐positivity probabilities, using an exchangeable correlation structure to account for within‐cohort correlations. Analyses were performed with (interactions between) age, amyloid‐status, and APOE‐e4 carriership as independent variables, stratified for syndrome diagnosis. Result The study included 5962 CN participants (7.5% tau‐PET‐positive), 1683 participants with mild cognitive impairment (MCI, 33.8% tau‐PET‐positive) and 2068 participants with a clinical diagnosis of dementia (62.1% tau‐PET‐positive) (Figure‐1). From age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 1.2% [95% CI: 0.9%‐1.5%] to 3.7% [2.3%‐5.1%] among CN amyloid‐negative participants; and from 16.4% [10.8%‐22.1%] to 20.5% [18.8%‐22.2%] among CN amyloid‐positive participants. Among amyloid‐negative participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 3.5% [1.6%‐5.3%] to 11.8% [7.1%‐16.5%] and from 12.6% [4.5%‐20.7%] to 15.9% [6.7%‐25.1%] respectively. In contrast, among amyloid‐positive participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity decreased from 66.5% [57.0%‐76.0%] to 48.3% [42.9%‐53.8%] and from 92.3% [88.7%‐95.9%] to 73.4% [67.5%‐79.3%] respectively. APOE‐e4 status primarily modulated the association of age with tau‐PET‐positivity estimates among CN and MCI amyloid‐positive participants (Figure‐2). Conclusion This large‐scale multi‐cohort study provides robust prevalence estimates of tau‐PET‐positivity, which can aid the interpretation of tau‐PET in the clinic and inform clinical trial designs.
Background A novel improvement to Quanterix Corporation Single molecule array (Simoa) SR‐X instrument has been shown to offer up to 100‐fold increased sensitivity compared with standard Simoa HD‐X and SR‐X instruments. We independently validated this increased sensitivity using the Simoa interleukin 17A (IL17A) assay. Method IL17A was measured in 32 paired Alzheimer’s disease (AD; n = 13) and control (CTRL; n = 19) serum and cerebrospinal fluid (CSF) samples. Mean IL17A concentrations were compared in both biofluids measured using four Simoa instruments ‐ one HD‐X instrument and three SR‐X instruments modified to improve the efficiency of reading beads. Result HD‐X quantified IL17A in 0% of CSF samples and 37.5% of serum samples, with mean serum IL17A concentrations of 0.126pg/mL in AD and 0.228pg/mL in CTRLs. In contrast, the modified SR‐X instruments A, B and C quantified CSF IL17A in 84.4%, 96.9% and 96.9% of CSF samples, respectively, with mean AD concentrations of 2.92fg/mL, 5.95fg/mL and 7.25fg/mL, respectively, and mean CTRL concentrations of 3.60fg/mL, 4.75fg/mL and 9.02fg/mL, respectively. Furthermore, the modified SR‐X instruments A, B and C all quantified IL17A in 100% of serum samples, with mean serum AD concentrations of 0.145pg/mL, 0.285pg/mL, and 0.249pg/mL, respectively, and mean CTRL concentrations of 0.300pg/mL, 0.406pg/mL and 0.362pg/mL, respectively. There were no statistically significant intra‐instrument differences between AD compared with CTRLs. All three modified SR‐X serum concentrations showed a strong positive statistically significant correlation with HD‐X serum concentrations. All three modified SR‐X serum concentrations also showed a strong positive statistically significant correlation with one another. Finally, all three modified SR‐X instruments showed no correlation between serum and CSF concentrations, in line with previous literature. Conclusion Increasing the bead reading efficiency of the SR‐X exhibits increased sensitivity compared with the standard Simoa HD‐X instrument, allowing the quantification of IL17A in CSF and a greater yield of serum samples.
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35 members
Gordon Stamp
  • Experimental Histopathology
Tammy MK Cheng
  • Biomolecular Modelling Lab
Gary Hong Chun Chung
  • Cell Biophysics Lab
Nil Ege
  • Tumour Cell Biology
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